Mizuma Takashi
Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Int J Pharm. 2009 Aug 13;378(1-2):140-1. doi: 10.1016/j.ijpharm.2009.05.044. Epub 2009 May 30.
The kinetic impact of intestinal glucuronidation metabolism on oral bioavailability (F) was assessed using reported human data of raloxifene, of which oral bioavailability was only 2%. Kinetic analysis showed that presystemic intestinal availability (Fpg) was 5.4%, whereas fraction absorbed (Ff) and hepatic availability (Fh) were 63% and 59.3%, respectively. Thus, Fpg was the lowest among factors, which affect oral bioavailability. In addition, Fpg was much lower than Fh, suggesting that intestinal glucuronidation metabolism has a greater impact on oral bioavailability than hepatic glucuronidation metabolism. It has been reported that UDP-glucuronosyltransferase (UGT) 1A1, UGT1A8, UGT1A9, and UGT1A10 are enzymes for raloxifene glucuronidation, and UGT1A8 and UGT1A10 are absent in the human liver, whereas UGT1A1, UGT1A8, UGT1A9, and UGT1A10 are present in the human intestine. Therefore, it is also suggested that intestinal glucuronidation catalyzed by UGTs, particularly UGT1A8 and UGT1A10, may play important roles in the first-pass metabolism, causing low oral bioavailability.
利用已报道的雷洛昔芬人体数据评估肠道葡萄糖醛酸化代谢对口服生物利用度（F）的动力学影响，雷洛昔芬的口服生物利用度仅为2%。动力学分析表明，肠前体药物的可利用性（Fpg）为5.4%，而吸收分数（Ff）和肝脏可利用性（Fh）分别为63%和59.3%。因此，Fpg是影响口服生物利用度的各因素中最低的。此外，Fpg远低于Fh，这表明肠道葡萄糖醛酸化代谢对口服生物利用度的影响大于肝脏葡萄糖醛酸化代谢。据报道，UDP-葡萄糖醛酸基转移酶（UGT）1A1、UGT1A8、UGT1A9和UGT1A10是雷洛昔芬葡萄糖醛酸化的酶，UGT1A8和UGT1A10在人肝脏中不存在，而UGT1A1、UGT1A8、UGT1A9和UGT1A10在人肠道中存在。因此，也有人提出，由UGTs催化的肠道葡萄糖醛酸化，尤其是UGT1A8和UGT1A10，可能在首过代谢中起重要作用，导致口服生物利用度较低。
